(1) Field of the Invention
The present invention relates to a process for the preparation of 3,4-dihydroxybutanoic acid and 3-hydroxy-.gamma.-butyrolactone therefrom starting with a pentose sugar source substituted in the 3-position, preferably in the chiral form. In particular, the process relates to the synthesis of (R)-3,4-dihydroxybutanoic acid and (R) 3-hydroxy-.gamma.-butyrolactone from a substituted L-pentose source. The process uses a base and a peroxide to convert the pentose source to chiral 3,4-dihydroxybutanoic acid. The chiral 3,4-dihydroxybutanoic acid can be further converted to 3-hydroxy-.gamma.-butyrolactone by acidification. The products are useful to the synthesis of various drugs and natural products.
(2) Description of Related Art
The current art on the oxidation of carbohydrates to 3,4-dihydroxybutanoic acid and derivatives describe the transformation of substituted hexoses which are usually only of the D-configuration which upon conversion yield only the 3,4-dihydroxybutanoic acid and derivatives in the (S)-configuration. In these reactions, chiral 3,4-dihydroxybutanoic acid and derivatives thereof are synthesized from carbohydrates by oxidation of 4-substituted hexoses with hydrogen peroxide. The chiral carbon atom is derived from the 5-position of the hexose sugar. Because most naturally occurring hexose sugars are of the D-configuration, this method is good only for preparation of (S)-3,4-dihydroxybutanoic acid and derivatives. In contrast to the position with hexose sugars, some pentose sugars such as xylose and arabinose occur in considerable amounts in the L-configuration.
There are methods for transforming 3,4-dihydroxybutanoic acid and derivatives to important molecules such as carnitine, however the process is extremely problematic starting from the (S)-derivatives because the stereochemistry at the 3-position has to be inverted. The prior art describes chemical and enzymatic processes for the preparation of the (S)-3,4-dihydroxybutanoic acid and derivatives by oxidation of sugars, but not for the preparation of (R)-3,4-dihydroxybutanoic acid and derivatives.
U.S. Pat. Nos. 4,994,597 and 5,087,751 to K. Inoue et al disclose methods for making optically active 3,4-dihydroxybutyric acid derivatives by reacting R-3-chloro-1,2-propanediol made by stereo selective microorganism decomposition of racemic 3-chloro-1,2-propanediol.
U.S. Pat. No. 5,319,110 to R. Hollingsworth discloses a process for synthesis of an internal cyclic ester such as a lactone by converting a hexose source, which contains hexose as a substituent and another sugar attached to the hexose substituent in the 4 position via (S)-3,4-dihydroxybutanoic acid as an intermediate. U.S. Pat. No. 5,374,773 to R. Hollingsworth discloses a process for the synthesis (S)-3,4-hydroxybutanoic salt by converting a hexose source which contains hexose as a substituent and another sugar attached to the hexose substituent in the 4 position via (S)-3,4-dihydroxybutyric acid as an intermediate. U.S. Pat. No. 5,292,939 to R. Hollingsworth discloses synthesis of (S)-3,4-dihydroxybutyric acid from substituted D-hexose.
(S)-3,4-dihydroxybutyric acid and derivatives, such as (S)-1,2,4 butanetriol that is formed by its reduction, are important 4-carbon compounds that are pivotal intermediates in the synthesis of various drugs and other natural products. These include the preparation of compounds such as eicosanoids (E. J. Corey et al. 1978. J. Amer. Chem. Soc. 100: 1942-1943), modified nucleic acid bases (H. Hayashi et al. 1973. J. Amer. Chem. Soc. 95: 8749-8757), the polyol function of macrolide antibiotics (Y. Mori et al. 1988. Tetrahedron Letts. 29: 5419-5422), and (-) aplysistatin, an anticancer agent (H. M. Shieh and G. D. Prestwich. 1982. Tetrahedraon Letts. 23: 4643-4646).
A common route to the (S)-3-hydroxy-.gamma.-butyric acid or butyrolactone equivalent used in the above synthesis involves the use of malic acid as the chiral raw material. This is reduced to a triol and the two vicinal hydroxyl groups protected by acetylization with acetone and an acid catalyst. The remaining primary hydroxyl group is then oxidized to an aldehyde or acid and the acetal group is then removed. Preparation of (R) and (S) isomers of gamma-lactone from (R) or (S) malic acid has also been described by Uchikawa et al. 1988. Bull. Chem. Soc. Jpn. 61: 2025-2029. These routes have been of academic interest because malic acid is reasonably expensive and two groups have to be reduced to the level of an alcohol and one then selectively oxidized. (S)-3-hydroxy-.gamma.-butyrolactone as a synthetic intermediate in the drug industry is a very expensive material.
Therefore, it is desirable to develop a process for transforming pentose sugars such as xylose and arabinose into useful building blocks for the preparation of chiral compounds for use in the drug, agri-chemical and advanced material science industries. In particular, it is desired that a method for oxidizing pentoses which would remove a 1 carbon from the reducing end and an oxygen from the 2-position give either the (R) or (S) isomer of 3,4-dihydroxybutanoic acid and derivatives, using essentially the same reaction and depending on whether the D or L pentose is used.